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ISOFORM-SPECIFIC EXPRESSION AND INDUCTION OF UDP-GLUCURONOSYLTRANSFERASE IN IMMUNOACTIVATED PERITONEAL MACROPHAGES OF THE RAT

Laboratory of Veterinary Biochemistry, Graduate School of Veterinary Medicine (Y.T., S.G., H.Y.), and Laboratory of Biology, Faculty of Environmental System (N.Y.), Rakuno Gakuen University, Ebetsu, Hokkaido, Japan; Expression and Molecular Regulation Research Group, Research Institute of Genome-based Biofactory, National Institute of Advanced Industrial Science and Technology, Tsukisamu-higashi, Toyohira-ku, Sapporo, Japan (Y.T., S.O.); and Graduate School of Science, Hokkaido University, Kita-ku, Sapporo, Japan (S.O.)

Phase I drug-metabolizing enzymes such as cytochrome P450 in immunocytes are known to play a role in metabolic activation of toxic and immunosuppressive compounds such as polycyclic aromatic hydrocarbon (PAH). UDP-glucuronosyltransferase (UGT), a drug-metabolizing phase II enzyme, accelerates elimination of these compounds; however, there is little information on the expression and function of UGT in immunocytes. In this study, we investigated the expressions of UGT isoforms in rat peritoneal macrophages and the role of UGT in macrophage functions. Expressions of UGT1A1, 1A6, and 1A7 were observed in macrophages by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. When macrophage cells cultured in plates were exposed to 1-naphthol and 3-hydroxybenzo-[a]pyrene (3-OH-B[a]P), these glucuronides increased in the medium, indicating that macrophages glucuronidated the chemicals. The production of the glucuronides of 1-naphthol and 3-OH-B[a]P was induced by lipopolysaccharide (LPS) treatment of the cultured macrophage cells. Northern blot analysis revealed that UGT1A7 mRNA was induced by LPS treatment. This result is the first evidence that a drug-metabolizing enzyme is induced by immunoactivation. The results indicated that macrophages can detoxify various toxic and immunosuppressive compounds with UGT, and that ability is enhanced by immunoactivation. We propose that macrophages contribute to protection against not only macromolecules as immunocytes but also small molecules such as the immunosuppressive agents PAHs in peripheral blood and interstitial tissues.